This invention relates to a new use for the drug mianserin or GB-94, which belongs to a group of compounds known broadly as "tetracyclics," and more particularly to the discovery of the marked effectiveness of this drug when employed as a pharmacologically active agent in the treatment of psychoses such as schizophrenia and neuroses such as anxiety syndrome.
Mianserin is represented by the following structural formula: ##STR2##
The invention further relates to the use of the pharmacologically active compound, mianserin and its use as an antipsychotic (neuroleptic) and antianxiety (anxiolytic) agent. For the sake of clarity, brevity and ease of understanding, the compound will hereinafter be referred to as GB-94 (this designation appears in the literature, for instance Proceedings of a Symposium on Depressive Illness and Experiences with a New Antidepressant Drug GB-94, editor T. Vossenaar -- Excerpta Medica).
Several years ago a group of "tetracyclic" compounds was developed by structural modification of the phenbenzamine molecule for use as antiserotonin and antihistamine drugs. In the animal, one of these compounds namely GB-94 was found to have particularly potent peripheral antihistamine-antiserotonin properties. This activity was confirmed in clinical trials using patients having allergic conditions, hay fever, asthma and migraine. However as the clinical trials did not demonstrate that GB-94 had any advantages over existing antiallergic drugs, the clinical use of this tetracyclic as an antiallergic drug was discontinued.
The subsequent search for potent antiserotonin compounds with minimal side effects to use in the treatment of manic patients, resulted in a renewed interest in these tetracyclics.
In order to determine whether the tetracyclic compound GB-94 had any significant CNS effects, a single rising dose tolerance study utilizing quantitative EEG was carried out. The results of this study established that:
1. GB-94 produces marked CNS effects as indicated by significant EEG alterations. Generally these changes are characterized by a decrease of alpha activity and a concomitant increase of slow and very fast beta activity. However, it was observed that in some subjects there was a marked increase of slow waves and decrease of fast activities in both the primary wave and first derivative measurements of the computer analysis. On the other hand, in other subjects, there was a decrease of the slow waves and an increase of the frequencies in the range of 20-40 cps in both the primary wave and first derivative measurements of digital computer period analysis.
2. The type of EEG alterations induced by GB-94 were, in some subjects, strikingly similar to those changes induced by antipsychotic (neuroleptic) compounds and in other subjects similar to those changes induced by the minor tranquilizers (anxiolytics).
Several biologically active derivatives of the piperazine are already known. Thus, U.S. Pat. No. 2,794,804 describes piperazines substituted at both nitrogen atoms and in the ring by a lower alkyl or hydroxyalkyl group. These compounds possess an oral vasodilating activity and exert an inhibiting action on adrenergic activity. U.S. Pat. No. 3,037,983 describes many other derivatives in which the two nitrogen atoms are substituted and in which a methyl group occurs in the nucleus, in .alpha.-position relative to the nitrogen atoms which also are possessed of an inhibitory effect on adrenergic activity.
In U.S. Pat. No. 3,534,041 related to similar derivatives, it is noted that the compounds of the piperazine type "...possess an oral vasodilating activity and exert an inhibiting action on adrenergic effect"... "have a dilating activity on the bronchi and are usable in the treatment of asthma." GB-94 (mianserin) which is included in the patent is described as exerting an anti-inflammatory, antiserotonic and antihistaminic, as well as a strong antiphlogistic activity. It is apparent that the latter patent teaches that only the corresponding intermediate precursors possess any antidepressive and tranquilizing activity. It is totally unexpected and highly surprising that antipsychotic (neuroleptic) and anxiolytic (minor tranquilizers) properties are present in the final product. Antiserotonins and antihistamines as a general rule do not exhibit anxiolytic and neuroleptic activities. It was only possible by utilizing the quantitative EEG, more specifically quantitative pharmaco-electroencephalography (QPEEG).TM. to establish the anxiolytic and neuroleptic properties of GB-94. Recently, the validity of quantitative pharmaco-EEG as a predictive method for psychotropic drugs was demonstrated (Itil, T. M., et al. Quantitative pharmaco-electroencephalography using frequency analyzer and digital computer methods in early drug evaluations; Smith, W. L., Drugs, Development and Brain Functions. Springfield, Ill, Charles C. Thomas, 1971, pp. 69-80). Using the QPEEG techniques, not only have the psychotropic properties of a series of compounds as predicted by animal pharmacology been confirmed, but more important as in the case of GB-94 it has become possible to predict the psychotropic properties of compounds for which such activity previously could not have been predicted by animal pharmacology (Itil, T.M. Quantitative pharmaco-electroencephalography in the discovery of a new group of psychotropic drugs, Diseases of the Nervous System, 33(8):557-559, 1972).